Structural Basis of Lipid Membrane Binding by Human Ferlins Article Swipe
Constantin Cretu
,
Aleksandar Chernev
,
Csaba Zoltán Kibédi Szabó
,
Vladimir Peña
,
Henning Urlaub
,
Tobias Moser
,
Julia Preobraschenski
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.01.25.634844
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.01.25.634844
Ferlins, ancient membrane proteins with a unique architecture, are central to multiple essential, Ca 2+ -dependent vesicle fusion processes. Despite numerous functional studies and their link to burdening human diseases, a mechanistic understanding of how these multi-C 2 domain proteins interact with lipid membranes to promote their remodeling and fusion is currently lacking. Here, we elucidate the near-complete cryo-electron microscopy structures of human myoferlin and dysferlin in their Ca 2+ and lipid-bound states. We show that ferlins adopt compact, ring-like tertiary structures achieved upon membrane binding. The top arch of the ferlin ring, comprising the C 2 C-C 2 D region, is rigid and varies little across the observed functional states. In contrast, the N-terminal C 2 B and the C-terminal C 2 F-C 2 G domains cycle between alternative conformations and, in response to Ca 2+ , close the ferlin ring, promoting tight interaction with the target membrane. Probing key domain interfaces validates the observed architecture and informs a model of how ferlins engage lipid bilayers in a Ca 2+ - dependent manner. This work reveals the general principles of human ferlin structures and provides a framework for future analyses of ferlin-dependent cellular functions and disease mechanisms.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.01.25.634844
- OA Status
- gold
- Cited By
- 1
- References
- 105
- Related Works
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- OpenAlex ID
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All OpenAlex metadata
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https://openalex.org/W4406868918Canonical identifier for this work in OpenAlex
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https://doi.org/10.1101/2025.01.25.634844Digital Object Identifier
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Structural Basis of Lipid Membrane Binding by Human FerlinsWork title
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preprintOpenAlex work type
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enPrimary language
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2025Year of publication
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2025-01-27Full publication date if available
- Authors
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Constantin Cretu, Aleksandar Chernev, Csaba Zoltán Kibédi Szabó, Vladimir Peña, Henning Urlaub, Tobias Moser, Julia PreobraschenskiList of authors in order
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https://doi.org/10.1101/2025.01.25.634844Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://resolver.sub.uni-goettingen.de/purl?gro-2/151208Direct OA link when available
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Basis (linear algebra), Chemistry, Membrane, Biophysics, Computational biology, Biochemistry, Mathematics, Biology, GeometryTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
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10Other works algorithmically related by OpenAlex
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